Current concepts of tumor-infiltrating lymphocytes in human malignancies

Tumor-infiltrating lymphocytes (TILs) develop as manifestations of the recognition and defense against malignant cells by the host immune system. TILs were literally defined as "tumor-infiltrating lymphocytes", which a posteriori locate within the tumor tissues. Although such cells can be found, they fail to control the growth of tumor. Many have proposed diverse mechanisms for dysfunction of TILs with regard to the roles of immunosurveillance against cancer. However, only a few cancer types, e.g. melanoma, have seen the benefits brought by activating these cells for immunotherapy. Functional defects of TILs have been linked to abnormalities of signaling molecules; however, there is conflicting data. The death of TILs was attributed to expression of cancer-derived FasL, PD-1 and RCAS1, and cancer-induced activation-induced cell death (AICD). Confirmed by studies using TILs and animal models, the compromise of tumor-specific immune responses was thought to result from not only mechanisms of clonal anergy but also exhaustion and/or deletion. Furthermore, functional cytotoxic CD8(+) TILs might be rendered incompetent by cancer-induced up-regulation of inhibitory NK receptors or proximal signaling abnormalities. Additionally, immune privilege was partly attributed to recruitment of regulatory T cells to the tumor sites. The failure of IL-2 signaling, which stands at the center of T cell functionalities, had been linked to the enzymatic activity of cancer-derived matrix metalloproteinases (MMPs). Finally, the exploitation of IDO expression, an important enzyme in pregnancy-related immunosuppression, by cancer cells might play a role in tumor immunity. The disparity of cancer types, origin, developmental stages and individual genetic backgrounds likely account for differences, or even contradictions, which might be the reason why immunotherapy works only on a few cancer types. Delineating the mechanisms behind functional defects of TILs can help not only boost chances of the development of a successful cure but understand the not fully identified roles played by immune system in the face of malignancies.     

Neutralizing antibody response and SARS severity

Using the Taiwan nationwide laboratory-confirmed severe acute respiratory syndrome (SARS) database, we analyzed neutralizing antibody in relation to clinical outcomes. With a linear mixed model, neutralizing antibody titer was shown to peak between week 5 and week 8 after onset and to decline thereafter, with a half-life of 6.4 weeks. Patients with a longer illness showed a lower neutralizing antibody response than patients with a shorter illness duration (p = 0.008). When early responders were compared with most patients, who seroconverted on and after week 3 of illness, the small proportion (17.4%) of early responders (antibody detectable within 2 weeks) had a higher death rate (29.6% vs. 7.8%) (Fisher exact test, p = 0.004), had a shorter survival time of <2 weeks (Fisher exact test, p = 0.013), and were more likely to be > 60 years of age (Fisher exact test, p = 0.01). Our findings have implications for understanding the pathogenesis of SARS and for SARS vaccine research and development.     

Variable pump flow-based Doppler ultrasound method: a novel approach to the measurement of access flow in hemodialysis patients

Decreasing vascular access flow (Qa) is an important predictor of future access thrombosis and malfunction for hemodialysis (HD) patients. Among all of the methods for determining Qa, the variable pump flow (VPF) Doppler method measures Qa according to the change in Doppler signal between the arterial and the venous needles under different pump flow. After this technique was combined with spectral analysis of Duplex Doppler imaging, the variable pump flow-based Doppler ultrasound method (VPFDUM) for Qa measurement was developed. This study compared the reproducibility and correlation of Qa measurements for three different methods-VPFDUM, ultrasound dilution method (UDM), and conventional Doppler ultrasound method (CDUM)-in 55 HD patients. The mean value of Qa by VPFDUM (870.8 +/- 412.0 ml/min) was close to that by UDM (868.6 +/- 417.9 ml/min) but higher than that by CDUM (either of the above values versus 685.1 +/- 303.6 ml/min; P < 0.005). The mean values of coefficient of variation were similar by VPFDUM (1.6%) and UDM (1.4%) but lower than that by CDUM (either of the above values versus 6.8%; P < 0.01). The correlation coefficient and intraclass correlation coefficient of the repeated Qa measurements by VPFDUM (0.985 and 0.993; P < 0.001) were also similar to those by UDM (0.992 and 0.995; P < 0.001) but slightly higher than those by CDUM (0.917 and 0.948; P < 0.005). Either the reproducibility of VPFDUM (r=0.98, P < 0.0001) or the correlation between VPFDUM and UDM (r=0.99, P < 0.0001) in Qa measurements is good. The unassisted patency of vascular access at 6 mo was significantly poorer in patients with Qa <500 ml/min than those with Qa >500 ml/min (13.6% versus 92.2%; P < 0.0001). In conclusion, VPFDUM is a noninvasive, accurate, and reliable procedure for Qa measurement and prediction of the prognosis of vascular access in HD patients.     

Irinotecan (CPT11) plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) as salvage therapy for metastatic colorectal cancer (MCRC) after failed oxaliplatin plus 5-FU and LV: a pilot study in Taiwan

BACKGROUND: Irinotecan (CPT11) has established activity against advanced colorectal cancer without cross-resistance with 5-fluorouracil + leucovorin-based therapy. We conducted this pilot study to evaluate the efficacy and tolerance of combination treatment with irinotecan and 5-fluorouracil (5-FU) for patients in whom combination treatment with oxaliplatin with 5-FU + leucovorin has failed. METHODS: Patients were enrolled in this study after oxaliplatin treatment had failed. The treatment protocol consisted of CPT11 (180 mg/m(2) for 90 min) on day 1 and a 2 h infusion of 200 mg/m(2) leucovorin followed by 400 mg/m(2) 5-FU as an intravenous bolus injection plus a 22 h continuous infusion of 600 mg/m(2) 5-FU. This regimen was repeated for two consecutive days every 2 weeks. RESULTS: A total of 18 patients were eligible for this study and in total 144 cycles of therapy (median eight cycles) were given to these patients. Four patients (22.2%; 95% CI: 8-36.4%) achieved an objective response of partial remission (PR) and an additional seven obtained stable disease (SD) status or minor response. The median duration of response was 8 months and 14 patients were alive at the end of the study. Hematological toxicity (neutropenia) was the most common serious side effect (29.2%), followed by gastrointestinal effects (diarrhea, 28.5%). Grade II-III diarrhea was experienced for at least one cycle by each patient. CONCLUSIONS: The results of treatment for patients after oxaliplatin failure are encouraging and this treatment protocol is also well tolerated by previously heavily treated patients.     

Non-viral human IL-10 gene expression reduces acute rejection in heterotopic auxiliary liver transplantation in rats

We studied nonviral delivery, expression, and the effect of the human interleukin-10 (Hu IL-10) gene on the rat model of heterotopic auxiliary liver transplantation (HALT). Two previous pilot studies showed remarkable expression of the Hu IL-10 gene in donor and recipient rats, and a decreasing effect of acute rejection in certain cases. In this study, we focused on the efficacy of Hu IL-10 gene expression to decrease acute rejection compared with cyclosporine A (CyA) in a HALT model. Three study groups and one control group were designed. Each group consisted of 6 DA donor and 6 Lewis recipient rats, which underwent HALT. In the control group, donors and recipients were not treated at all. In group II, recipients were treated with one dose of CyA. In group III, donors were treated with Hu IL-10 plasmid. In group IV, donors were treated with Hu IL-10 plasmid, and recipients were treated with one dose of CyA. Rejection was established by histopathology: it revealed 100% rejection in control and 33.3% rejection in study groups II, III, and IV. Human IL-10 gene expression prevented acute rejection with the same efficacy as CyA in the HALT model in rats.     

Rapid communication: pure robot-assisted laparoscopic ureteral reimplantation for ureteral stricture disease: case report

BACKGROUND AND PURPOSE: The role of the da Vinci robot is slowly being defined in minimally invasive urologic surgery. We report its use in the management of ureteral stricture disease. CASE REPORT: A 42-year-old man with recurrent kidney stone disease was found to have a left distal-ureteral stricture. After failure of endoscopic treatment, a robot-assisted laparoscopic ureteral reimplantation was performed. The total operative time was 210 minutes. The estimated blood loss was <50 mL. There were no intraoperative or postoperative complications. Total analgesic use was 30 mg of morphine. The hospital stay was 5 days. CONCLUSION: Pure robot-assisted laparoscopic ureteral reimplantation is a safe and feasible approach to the management of ureteral stricture disease.